Cerebral ischemia, most notably in the form of stroke, is a leading cause of long-term disability and ranks as the third leading cause of death in the United States. A fundamental understanding of cerebral ischemia and the inciting cellular dysfunction is imperative for the development of new therapies to combat this growing epidemic. Ischemic preconditioning (IPC) is a neuroprotective mechanism whereby the induction of mild ischemic insults protects against subsequent lethal ischemia. IPC has been demonstrated to ameliorate cerebral ischemia following stroke in rodent models, although the signaling pathways involved are not fully understood. Nuclear factor erythoid-2 related factor (Nrf2) is a transcriptin factor involved in protecting the cell from the damaging effects of oxidative stress. Nrf2 has been suggested to be activated through IPC and may help precondition the brain, conferring neuroprotection following an ischemic insult. Nrf2 can also be activated by sulforaphane, an isothiocyanate found in cruciferous vegetables, and fumaric acid ester, an immune- modulator used in psoriasis treatment. Both sulforaphane and fumaric acid ester have been shown to be safe in humans; however, no clinical studies with these agents are being conducted to alleviate stroke. Therefore, the central hypothesis of this proposal is that Nrf2 is a key mediator of IPC-induced neuroprotection, and that Nrf2 preconditioning can reduce morbidity following stroke. The objectives of this application are to: (1) Identify if Nrf2 activation and nuclear translocatio are regulated by protein kinase C (PKC) and sirtuins (family of protein/histone deacetylases), specifically sirtuin 1 (SIRT1), following IPC; (2) Determine the mechanism(s) of Nrf2-mediated neuroprotection, primarily its effects on synaptic mitochondria; and (3) Determine if pharmacologic preconditioning with fumaric acid ester and sulforaphane can mimic IPC-induced neuroprotection following focal cerebral ischemia in a rodent model. These proposed studies will enhance our understanding of IPC, and how Nrf2 can be exploited to develop novel prophylactic therapy for the treatment of cerebral ischemia.